The invention relates to the field of nicotine mucosal sprays, to compositions comprising nicotine that can be administered in a mucosal spray form and to methods and uses therefore. In one embodiment, the invention relates to compositions and methods useful for subjects who wish to reduce tobacco smoking.
Due to the reported harmful effects of tobacco smoke and also due to the current social attitudes to smoking, resulting in ever-increasing smoke-free public areas, there is great pressure on tobacco smokers to stop smoking or to find a more socially acceptable alternative. To achieve these goals various forms of nicotine-replacement therapy have been suggested. One such therapy is a nicotine nasal spray (NNS).
A commercially available NNS has a nicotine (concentration of 10 mg/ml (Nicotrol NS(copyright), Pharmacia and Upjohn) and is described in U.S. Pat. No. 5,656,255 (the ""255 patent). The ""255 patent teaches a NNS with a lower limit of nicotine concentration of 10 mg/ml and a preferred concentration of 20 mg/ml (1). Studies using the 10 mg/ml product show that it is an effective aid to quitting smoking (2-9), especially for heavy smokers (2). Recent studies show that, in heavy smokers who successfully quit smoking while using 10 mg/ml NNS, venous plasma nicotine levels were approximately two-thirds the level seen while smoking (9). Therefore, 10 mg/ml NNS is an effective nicotine replacement therapy in which plasma nicotine levels reach the range where most of the nicotine withdrawal symptoms are avoided (10, 11). Studies leading to the ""255 patent suggested that a nicotine concentration of 10 mg/ml was the lower limit capable of delivering sufficient nicotine to the blood plasma (⅔ of nicotine level seen while smoking) to avoid withdrawal symptoms.
Despite its demonstrated usefulness as a stop smoking aid, 10 mg/ml NNS causes many undesirable symptoms, the most common and severe of which are rhinorrhea (runny nose) and sneezing (2). Although these symptoms tend to moderate with continued use of 10 mg/ml NNS, many smokers stop using 10 mg/ml NNS because of the symptoms and, consequently, fail in their efforts to quit smoking (9).
Sutherland et al (2) have shown that heavy smokers (defined as those who score between 7 and 11 on the Fagerstrom Nicotine Tolerance Scale (12)) were more likely to quit smoking when using 10 mg/ml NNS than were lighter smokers who had lower plasma nicotine levels during unrestricted smoking. The lighter smokers (defined as those who score less than 7 on the Fagerstrom Scale) were as likely to quit smoking with placebo nasal spray as they were with 10 mg/ml NNS.
Although Schuh et al (13) assessed different doses of NNS they varied the dose by varying the number of sprays of 10 mg/ml NNS and not by varying the nicotine concentration in the spray. Unpublished observations from the inventors and observations published by Schuh et al (13) suggest that nasal symptoms are relatively independent of the number of sprays into the lose (one 0.05 ml spray of 10 mg/ml delivering 0.5 mg produces a response similar to two sprays of 10 mg/ml delivering 1 mg nicotine).
Perkins and his group (14-18) have studied the effects of various doses of nicotine nasal spray on physiological and behavioral function. Perkins"" nasal spray delivery procedure is self-described as a method for research purposes (17) and not as a method suitable for clinical nasal spray trials, such as that conducted by Sutherland et al (2) and by the present inventors (9). Flerkins"" technique involves spraying eight times (four sprays into each nostril) over a 2 minute period (18). The total volume of the eight sprays is 1.4 ml (0.175 ml/spray) and this volume stays constant. Such high volumes could not be used in a commercial product since considerable skill and a laboratory environment are requited to deliver and retain 1.4 ml and not have it run out the nose or drip backwards into the nasal pharynx.
In U.S. Pat. No. 5,721,257, Baker et al (19) describe a combination nicotine replacement therapy consisting of a nicotine skin patch to provide a steady level of blood nicotine which is supplemented, as required, by a nicotine nasal spray (nicotine concentration between 1 and 10 mg/ml) to provide transient increases in blood nicotine level of about 5 ng/ml. U.S. Pat. No. 5,721,257 (the ""257 patent) teaches that it is the combination of nicotine replacement therapies that is effective and not the nicotine nasal spray. One disadvantage of the ""257 patent is that it requires two different therapies. Another is that it is addressed to a nasal aerosol that is inhaled into the bronchioles of the lungs.
Accordingly, there remains a need for a nicotine therapy for assisting persons in stopping smoking and in reducing their desire to smoke.
The present invention provides novel methods and compositions for nicotine therapy. In one embodiment, the invention provides a composition for nasal administration of nicotine to a subject effective in increasing the nicotine plasma concentration of the subject to a level effective to assist the subject in quitting smoking and that results in reduced nasal symptoms as compared with other nicotine nasal sprays. Preferably, the composition results in minimal, and more preferably no nasal symptoms.
In a preferred embodiment, the invention provides a nicotine spray composition for administration to the nasal mucosa of a subject comprising a solution of nicotine or a pharmaceutically acceptable s It thereof in a pharmaceutically acceptable solvent, the solution having a nicotine concentration less than 10 mg/ml, preferably 1 to less than 9 mg/ml, more preferably from a out mg/ml, more preferably form about 5 to about 9.9 mg/ml. In a preferred embodiment of the invention, the pharmaceutically acceptable solvent is phosphate buffered saline. In another embodiment the pH of the solution is between about 5.0 and 8.0, more preferably between about 6.0 to 7.5 and most preferably about 7.0. The term xe2x80x9caboutxe2x80x9d as used herein refers to +/xe2x88x9210% of the pH value.
In another embodiment, the invention provides a method that enables a subject to stop smoking and decreases the desire of a subject to smoke, the method comprising administering to the subject one source of an effective amount of nicotine, the source being in the form of a nicotine nasal spray composition that can be administered to the nasal mucosa of the subject, the composition comprising droplets having a size of about 10 or more microns and a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent, said solution having a nicotine concentration less than 9 mg/m. In a particular embodiment, the nicotine solution has a pH in the range of about 5.0 to 8.0, preferably between about 6.0 to 7.5 and most preferably about 7.0.
In another embodiment, the nicotine nasal spray composition of the invention can be used to reduce nasal symptoms associated with the administration of nicotine to the nasal mucosa, the method comprising administering the composition of the invention to the nasal mucosa of a subject. In a preferred embodiment the nicotine nasal spray is in the form of droplets having a size of about 10 or more microns and is a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent, the solution having a nicotine concentration less than 10 mg/ml and, preferably, a nicotine concentration in the range of about 5 mg/ml to less than 10 mg/ml. The term xe2x80x9caboutxe2x80x9d as used herein refers to +/xe2x88x9210% of the concentration value.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.